βd-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it

ABSTRACT

A βd-Crystalline form of ivabradine hydrochloride of formula (I): 
                         
characterized by its powder X-ray diffraction data.
 
     Medicinal products containing the same which are useful as bradycardics.

The present invention relates to the new βd-crystalline form of ivabradine hydrochloride of formula (I), to a process for its preparation and to pharmaceutical compositions containing it.

Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP 0 534 859.

In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light or oxygen level.

The patent specification EP 0 534 859 describes a synthesis process for ivabradine and its hydrochloride. However, that document does not specify the conditions for obtaining invabradine in a form that exhibits those characteristics in a reproducible manner.

The Applicant has now found that a particular salt of ivabradine, the hydrochloride, can be obtained in a crystalline form that is well defined and that exhibits valuable characteristics of stability and processability.

More specifically, the present invention relates to the βd-crystalline form of ivabradine hydrochloride, which is characterised by the following powder X-ray diffraction diagram measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts), ray area (expressed in counts×degrees), ray width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å):

Angle Area 2 theta Height (counts × FWHM Interplanar Ray no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.0 244 80 0.3346 22.139 2 5.9 377 56 0.1506 14.829 3 6.9 94 50 0.5353 12.835 4 9.2 1975 293 0.1506 9.623 5 11.8 136 27 0.2007 7.473 6 12.5 1826 241 0.1338 7.083 7 13.6 1834 303 0.1673 6.491 8 14.5 51 20 0.4015 6.119 9 16.0 1441 214 0.1506 5.525 10 17.3 4472 738 0.1673 5.134 11 18.4 546 108 0.2007 4.808 12 19.6 1025 169 0.1673 4.524 13 20.0 688 91 0.1338 4.448 14 20.4 1027 186 0.184 4.362 15 21.4 102 24 0.2342 4.143 16 22.3 1903 283 0.1506 3.990 17 22.8 674 89 0.1338 3.897 18 23.0 623 62 0.1004 3.866 19 24.4 845 56 0.0669 3.647 20 25.0 3749 557 0.1506 3.554 21 25.5 512 84 0.1673 3.497 22 26.6 289 76 0.2676 3.346 23 28.3 275 91 0.3346 3.151 24 29.1 126 21 0.1673 3.066

The invention relates also to a process for the preparation of the βd-crystalline form of ivabradine hydrochloride, which process is characterised in that a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallisation is complete, and the crystals thereby formed are collected and dehydrated.

-   -   In the crystallisation process according to the invention it is         possible to use ivabradine hydrochloride obtained by any         process, for example ivabradine hydrochloride obtained by the         preparation process described in patent specification EP 0 534         859.     -   The solution may advantageously be seeded during the cooling         step.

The invention relates also to pharmaceutical compositions comprising as active ingredient the βd-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, sublingual (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions.

The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. That dosage varies from 1 to 500 mg per day in one or more administrations.

The following Examples illustrate the invention.

The X-ray powder diffraction spectrum was measured under the following experimental conditions:

-   -   PANalytical X'Pert Pro diffractometer, X'Celerator detector,         temperature-regulated chamber,     -   voltage 45 kV, intensity 40 mA,     -   mounting θ-θ,     -   nickel (Kβ) filter,     -   incident-beam and diffracted-beam Soller slit: 0.04 rad,     -   fixed angle of divergence slits: ⅛°,     -   mask: 10 mm,     -   antiscatter slit: ¼°,     -   measurement mode : continuous from 3° to 30°, in increments of         0.017°,     -   measurement time per step: 19.7 s,     -   total time: 4 min 32 s,     -   measurement speed: 0.108°/s,     -   measurement temperature: ambient.

EXAMPLE 1 βd-Crystalline Form of Ivabradine Hydrochloride

720 ml of purified water are preheated to 50° C., and then 250 g of ivabradine hydrochloride obtained according to the process described in the patent specification EP 0 534 859 are added in portions, with stirring, and the mixture is heated at 74° C. until dissolution is complete. The resulting clear solution is heated for 2 more hours at 74° C. and is then progressively cooled, first to 40° C., and then to ambient temperature. The solution is subsequently stored at ambient temperature for 2 days, and then the solid suspension is spread out in a thin layer on a crystallisation plate. The excess water is driven off under a gentle current of nitrogen.

The product thereby obtained is dehydrated by progressively heating at a rate of 5° C./min up to a temperature of 80° C.

X-Ray Powder Diffraction Diagram:

The X-ray powder diffraction profile (diffraction angles) of the βd-form of ivabradine hydrochloride is given by the significant rays collated in the following table:

Angle Area 2 theta Height (counts × FWHM Interplanar Ray no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.0 244 80 0.3346 22.139 2 5.9 377 56 0.1506 14.829 3 6.9 94 50 0.5353 12.835 4 9.2 1975 293 0.1506 9.623 5 11.8 136 27 0.2007 7.473 6 12.5 1826 241 0.1338 7.083 7 13.6 1834 303 0.1673 6.491 8 14.5 51 20 0.4015 6.119 9 16.0 1441 214 0.1506 5.525 10 17.3 4472 738 0.1673 5.134 11 18.4 546 108 0.2007 4.808 12 19.6 1025 169 0.1673 4.524 13 20.0 688 91 0.1338 4.448 14 20.4 1027 186 0.184 4.362 15 21.4 102 24 0.2342 4.143 16 22.3 1903 283 0.1506 3.990 17 22.8 674 89 0.1338 3.897 18 23.0 623 62 0.1004 3.866 19 24.4 845 56 0.0669 3.647 20 25.0 3749 557 0.1506 3.554 21 25.5 512 84 0.1673 3.497 22 26.6 289 76 0.2676 3.346 23 28.3 275 91 0.3346 3.151 24 29.1 126 21 0.1673 3.066

EXAMPLE 2 Pharmaceutical Composition

Formula for the preparation of 1000 tablets each containing 5 mg of ivabradine base:

Compound of Example 1 5.39 g Maize starch 20 g Anhydrous colloidal silica 0.2 g Mannitol 63.91 g PVP 10 g Magnesium stearate 0.5 g 

1. A βd-Crystalline form of ivabradine hydrochloride of formula (I):

exhibiting essentially the following powder X-ray diffraction data, measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts), ray area (expressed in counts x degrees), ray width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å): Angle Area 2 theta Height (counts × FWHM Interplanar Ray no. (degrees) (counts) degrees) (degrees) distance (Å) 1 4.0 244 80 0.3346 22.139 2 5.9 377 56 0.1506 14.829 3 6.9 94 50 0.5353 12.835 4 9.2 1975 293 0.1506 9.623 5 11.8 136 27 0.2007 7.473 6 12.5 1826 241 0.1338 7.083 7 13.6 1834 303 0.1673 6.491 8 14.5 51 20 0.4015 6.119 9 16.0 1441 214 0.1506 5.525 10 17.3 4472 738 0.1673 5.134 11 18.4 546 108 0.2007 4.808 12 19.6 1025 169 0.1673 4.524 13 20.0 688 91 0.1338 4.448 14 20.4 1027 186 0.184 4.362 15 21.4 102 24 0.2342 4.143 16 22.3 1903 283 0.1506 3.990 17 22.8 674 89 0.1338 3.897 18 23.0 623 62 0.1004 3.866 19 24.4 845 56 0.0669 3.647 20 25.0 3749 557 0.1506 3.554 21 25.5 512 84 0.1673 3.497 22 26.6 289 76 0.2676 3.346 23 28.3 275 91 0.3346 3.151 24 29.1 126 21 0.1673  3.066.


2. A process for the preparation of the βd-crystalline form of ivabradine hydrochloride of claim 1, wherein a mixture of ivabradine hydrochloride and water or a mixture of ivabradine hydrochloride, isopropanol and water is heated until dissolution is complete and is then progressively cooled until crystallization is complete, and the crystals thereby formed are collected and then dehydrated.
 3. The process of claim 2, wherein the solution of ivabradine hydrochloride is seeded during the cooling step.
 4. A solid pharmaceutical composition comprising as active ingredient the βd-crystalline form of ivabradine hydrochloride of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.
 5. A method for treating a condition selected from angina pectoris, myocardial infarct and heart failure, such method comprising administering to a living animal body, including a human, a therapeutically effective amount of a βd-crystalline form of ivabradine hydrochloride of claim
 1. 